The development of statistical methods for detecting natural selection at the molecular level has made it possible to investigate the evolutionary forces that shape patterns of DNA sequence variation, and the genomic scale at which selection at one site influences patterns of variation at linked neutral sites. The purpose of the proposed study is to use natural populations of the deer mouse, Peromyscus maniculatmx as a model system to investigate the joint effects of selection, recombination, and gene flow in shaping the pattern of DNA sequence variation underlying physiological adaptation to high altitude. This study will involve a molecular genetic analysis of a two-locus a-globin polymorphism in populations of P. maniculatw that are distributed across steep elevational gradients in montane regions of western North America. The objectives of the Andy are (1) to document geographic patterns of sequence variation in the a-globin gene region of P. maniculatus by surveying mice sampled across three separate elevational transects; (2) to test for evidence of natural selection on a- globin variation using an array of newly developed statistical methods; (3) to determine the strength of epistatic selection relative to the rate of recombination between the two closely linked a-globin loci; and (4) to determine the strength of selection on a-globin variation relative to the rate of countervailing gene flow between high and low-altitude populations. This study will provide a unique opportunity to investigate adaptive variation in an important biochemical phenotype at the DNA sequence level.